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Oncotarget Jun 2024Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose)...
Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.
Topics: Humans; Decitabine; Pancreatic Neoplasms; Drug Synergism; Cell Line, Tumor; Histone Deacetylase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Azacitidine; Apoptosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38829622
DOI: 10.18632/oncotarget.28588 -
Oncotarget Jun 2017Elderly patients with acute myeloid leukemia (AML) have limited treatment options concerned about their overall fitness and potential treatment related mortality.... (Meta-Analysis)
Meta-Analysis Review
Elderly patients with acute myeloid leukemia (AML) have limited treatment options concerned about their overall fitness and potential treatment related mortality. Although a number of clinical trials demonstrated benefits of decitabine treatment in elderly AML patients, the results remains controversial. A meta-analysis was performed to evaluate efficacy and safety of decitabine in treatment of elderly AML patients. Eligible studies were identified from PubMed, Web of Science, Embase and Cochrane Library. Nine published studies were included in the meta-analysis, enrolling 718 elderly AML patients. The efficacy outcomes were complete remission (CR), overall response rate (ORR) and overall survival (OS). Safety was evaluated based on treatment related grades 3-4 adverse events (AEs) and early death (ED) rate. Pooled estimates with 95% confidence interval (CI) for CR, ORR and OS were 27% (95% CI 19%-36%), 37% (95% CI 28%-47%) and 8.09 months (95% CI 5.77-10.41), respectively. The estimated treatment related early death (ED) incidences were within 30-days 7% (95% CI 2%-11%) and 60-days 17% (95% CI 11%-22%), respectively. Thrombocytopenia was the most common grades 3-4 AEs. Subgroup analyses of age, cytogenetics risk, AML type and bone marrow blast percentage showed no significant differences of treatment response to decitabine. In conclusion, decitabine is an effective and well-tolerated therapeutic alternative with acceptable side effects in elderly AML patients.
Topics: Aged; Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Humans; Leukemia, Myeloid, Acute; Male
PubMed: 28489568
DOI: 10.18632/oncotarget.17241 -
Current Opinion in Oncology Nov 2008Two demethylating agents are approved in myelodysplastic syndromes (MDS): 5-azacitidine and 5-aza-2'-deoxycitidine (decitabine). These drugs are structurally related and... (Review)
Review
PURPOSE OF REVIEW
Two demethylating agents are approved in myelodysplastic syndromes (MDS): 5-azacitidine and 5-aza-2'-deoxycitidine (decitabine). These drugs are structurally related and induce DNA hypomethylation. Aberrant DNA methylation is associated with gene silencing. It is proposed that hypomethylating agents work by inducing reexpression of epigenetically silenced genes. Here, we provide an up-to-date summary of the clinical experience with these drugs.
RECENT FINDINGS
5-Azacitidine and decitabine were approved in the United States based on clinical responses, but no effect on survival was documented. Recent results from a phase III study have indicated that treatment of patients with higher risk MDS with 5-azacitidine results in significant improvement in overall survival. Results of a randomized survival study of decitabine should be available in 2008. Reports of combination epigenetic therapies (a hypomethylating agent with a histone deacetylase inhibitor) indicate that these have significant activity in patients with MDS/acute myelogenous leukemia. Randomized studies are testing the concept that the combinations are superior to single-agent therapy.
SUMMARY
Demethylating agents are the standard of care for patients with higher risk MDS and the only agent known to improve the natural history of MDS. Further work in new combination therapies may result in further advances in the care of patients with MDS.
Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clinical Trials as Topic; DNA Methylation; Decitabine; Epigenesis, Genetic; Gene Silencing; Humans; Leukemia; Myelodysplastic Syndromes; Risk; Treatment Outcome; Valproic Acid
PubMed: 18841054
DOI: 10.1097/CCO.0b013e328313699c -
Cancer Medicine Apr 2023There is an urgent need for effective treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R-DLBCL). This trial investigated the efficacy of... (Clinical Trial)
Clinical Trial
BACKGROUND
There is an urgent need for effective treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R-DLBCL). This trial investigated the efficacy of decitabine in combination with rituximab, cisplatin, cytarabine, dexamethasone (RDHAP) in R/R-DLBCL.
METHODS
56 patients were divided into two groups (decitabine-RDHAP group. n = 35; RDHAP group, n = 21). The primary endpoints were the overall response rate (ORR) and duration of remission (DOR). Secondary objectives were toxicity, progression-free survival (PFS), and overall survival (OS).
RESULTS
The ORR was 40% and 33% for decitabine-RDHAP and RDHAP groups, respectively, with no difference between the groups. The DOR for the decitabine-RDHAP regimen was higher than that for the RDHAP regimen (p = 0.044). After a median follow-up of 12.0 months, the median PFS and OS were 7.0 and 17.0 months for in the decitabine-RDHAP group and 5.0 and 9.0 months in the RDHAP group with no significant differences between the two groups (p = 0.47, 0.17). The incidence of adverse events was not significantly different between groups.
CONCLUSION
The decitabine-RDHAP regimen is effective and well tolerated, and is a promising salvage regimen for R/R-DLBCL.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Decitabine; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Rituximab; Treatment Outcome
PubMed: 36695162
DOI: 10.1002/cam4.5615 -
Cancer Immunology, Immunotherapy : CII Jul 2023Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable...
BACKGROUND
Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution.
METHOD
We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T.
RESULTS
Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T.
CONCLUSION
CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML.
Topics: Humans; Decitabine; Leukemia, Myeloid, Acute; Aminopyridines; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 36932256
DOI: 10.1007/s00262-023-03422-6 -
PloS One 2022DNA methylation regulates epigenetic gene expression in ischemic stroke. Decitabine attenuates ischemic stroke by inhibiting DNA methylation. However, the underlying...
DNA methylation regulates epigenetic gene expression in ischemic stroke. Decitabine attenuates ischemic stroke by inhibiting DNA methylation. However, the underlying mechanism of this effect is not known. A model of ischemic stroke in Sprague-Dawley rats was induced through middle cerebral artery occlusion followed by reperfusion step. The rats were randomly treated with decitabine or vehicle by a one-time intraperitoneal injection. Sham rats received similar treatments. Four days after treatment, the rats were perfused with saline or 4% paraformaldehyde after which the brain was excised. DNA methylation level and brain infarct volume were determined by dot blot and histochemistry, respectively. The cellular co-localization and quantitative analysis of DNA methylation were assessed by immunohistochemistry and expression levels of cdkn1b (p27) mRNA and protein were measured by qRT-PCR and immunohistochemistry, respectively. The proliferation of astrocytes and number of neurons were determined by immunohistochemistry. Rats treated with decitabine showed hypomethylation and reduced infarct volume in the cortex. DNA methylation was decreased in astrocytes. Decitabine upregulated p27 mRNA and protein expression levels and attenuated the proliferation of astrocytes in vivo and vitro. Decitabine promotes p27 gene expression possibly by inhibiting its DNA methylation, thereby decreases the proliferation of astrocytes, neuronal death and infarct volume after ischemic stroke.
Topics: Animals; Astrocytes; Brain Ischemia; Cell Proliferation; Decitabine; Infarction, Middle Cerebral Artery; Ischemic Stroke; RNA, Messenger; Rats; Rats, Sprague-Dawley; Stroke
PubMed: 35917376
DOI: 10.1371/journal.pone.0272482 -
Cells Aug 2020Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted... (Review)
Review
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.
Topics: Animals; Antimetabolites, Antineoplastic; Azacitidine; Cell Line, Tumor; DNA Methylation; Decitabine; Epigenesis, Genetic; Humans; Urinary Bladder Neoplasms
PubMed: 32784599
DOI: 10.3390/cells9081850 -
Asian Pacific Journal of Cancer... Jun 2023Epigenetic changes such as histone deacetylation and DNA methylation play to regulate gene expression. DNA methylation plays a major role in cancer induction via...
UNLABELLED
Epigenetic changes such as histone deacetylation and DNA methylation play to regulate gene expression. DNA methylation plays a major role in cancer induction via transcriptional silencing of critical regulators such as tumor suppressor genes (TSGs). One approach to inhibit TSGs inactivation is to use chemical compounds, DNA methyltransferase inhibitors (DNMTIs). Previously, we investigated the effect of 5-aza-2'-deoxycytidine (5 AZA CdR or decitabine) on colon cancer and hepatocellular carcinoma cell lines. The present study aimed to investigate the effect of 5 AZA CdR on extrinsic (DR4, DR5, FAS, FAS-L, and TRAIL genes), intrinsic [pro- (Bax, Bak, and Bim) and anti- (Bcl-2, Bcl-xL, and Mcl-1) apoptotic genes], and JAK/STAT (SOCS1, SOCS3, JAK1, JAK2, STAT3, STAT5A, and STAT5B genes) pathways in neuroblastoma (IMR-32, SK-N-AS, UKF-NB-2, UKF-NB-3, and UKF-NB-4) and glioblastoma (SF-767, SF-763, A-172, U-87 MG, and U-251 MG) cell lines.
MATERIALS AND METHODS
The neuroblastoma and glioblastoma cells were cultured and treated with 5 AZA CdR. To determine cell viability, cell apoptosis, and the relative gene expression level, MTT assay, flow cytometry assay, and qRT-PCR were done respectively.
RESULTS
5 AZA CdR changed the expression level of the genes of the extrinsic, intrinsic, and JAK/STAT pathways by which induced cell apoptosis and inhibited cell growth in neuroblastoma and glioblastoma cell lines.
CONCLUSION
5 AZA CdR can play its role through extrinsic, intrinsic, and JAK/STAT pathways to induce cell apoptosis.
Topics: Humans; Decitabine; Janus Kinases; Glioblastoma; Signal Transduction; STAT Transcription Factors; Azacitidine; Cell Line; DNA Methylation; Neuroblastoma; Deoxycytidine; Cell Line, Tumor
PubMed: 37378911
DOI: 10.31557/APJCP.2023.24.6.1841 -
Journal For Immunotherapy of Cancer Jan 2022The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid...
BACKGROUND
The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.
METHODS
We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).
RESULTS
In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.
CONCLUSION
Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Decitabine; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Pilot Projects; Recurrence
PubMed: 35017151
DOI: 10.1136/jitc-2021-003392 -
Cells Apr 2021Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger...
Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.
Topics: Biomarkers; DNA Methylation; Decitabine; Granuloma; Humans; Immunity; Inflammation; Macrophages; Monocytes; Mycobacterium; Phenotype
PubMed: 33921194
DOI: 10.3390/cells10040868